Chronic neuropathic pain following spinal cord injury (SCI) is a particularly challenging clinical target, as traditional analgesic drugs are only marginally effective at best, and fraught with untoward side effects owing to the high doses required. In addition to direct interference in the quality of life of these patients, the presence of untreated pain can limit participation in rehabilitation programs, resulting in poorer long-term prognosis and reduced functional recovery. Our laboratory has been evaluating traditional and non-traditional analgesics alone and in combinations for their ability to reduce neuropathic pain symptoms in a spinal clip compression model for SCI pain. This model produces persistent SCI pain symptoms, and demonstrates the ability to successfully distinguish pharmacologic agents with modest clinical efficacy from those reported to be ineffective in reducing clinical SCI pain. Marine cone snail peptides (conopeptides) have emerged as particularly promising candidates for this indication. Cone snails produce a number of novel peptides with selective ion channel blocking activity, and have become a major focus for new drug development in the treatment of CNS injury and disease. Among those potentially targeting pain pathways are the omega- conopeptide MVIIA, a peptide with N-type Ca2+ channel blocking activity (which has reached FDA approval as derivative Prialt in the treatment of severe pain) and conantokin-G (conG), a peptide with NMDA antagonist activity. Recent findings in our lab showed robust dose-dependent amelioration of pain responses following bolus intrathecal injection of these conopeptides, without apparent untoward side effects, and a highly potent synergistic pain reduction when used together in combination. These findings are remarkable in light of the difficulty in obtaining even modest effects of other drug combinations in this model or in clinical SCI pain reports. The goal of this exploratory/developmental R21 proposal in response to PA-10-007 (Mechanisms, models, measurement, & management in pain research) is to 1) explore the potential for long-term intrathecal delivery of conopeptide combinations to alleviate chronic SCI pain, and 2) to develop a means for providing sustained conopeptide delivery using gene therapy or transplanted cells. Specific aims to accomplish this are 1) To characterize neuropathic pain-reducing ability and effective dosing, time-course, and side effects of chronic conopeptide administration; 2) To evaluate the potential for long-term delivery of conopeptides via gene therapy or cell-based strategies. Initial studies will focus on adult bone marrow stem cells, which can be autologously derived and are currently being developed in clinical trials for SCI and other indications. Adeno- associated virus (AAV)-mediated delivery will also be explored in these initial studies, owing to its reported safety and use in clinical trials for other neurological disorders. If successful, this project should accelerate the process of bringing effective analgesic therapies to spinal cord injured patients, and advance novel high-impact strategies in the therapeutic management of debilitating chronic pain. PUBLIC HEALTH RELEVANCE: Chronic pain following spinal cord injury is estimated to occur in up to 70% of patients, with at least one-third rating it as so severe that it is their primary impediment to participation in daily activities and social well-being. Neuropathic pain following SCI is particularly resistant to treatment, and its persistence can limit participation in rehabilitation therapies and further reduce functional recovery. Thus there is a critical need for identifying effective long-term therapies for alleviating chronic SCI pain. The proposed studies will evaluate the potential for novel and remarkably selective naturally-derived peptides (conopeptides), delivered on a long-term basis via gene therapy or cell transplantation approaches, to ameliorate chronic pain following spinal cord injury.